78P Cancer immunotherapy: Rejuvenation of anti-cancer response by immune checkpoint blockade using novel multifunctional nanoparticle to block CTLA-4 and eliminate ICER

Abstract

Our strategy for removal of immune tolerance is to elicit antitumor immunity in several thousands of T cells using mesoporous silica nanoparticle (MSN) targeting potent immune checkpoint inhibitors irrespective of their cellular localization; such as - inducible cAMP early repressor (ICER) in the nucleus and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on T cell`s surface. Thus, the aim of our project is to elicit antitumor immunity against melanoma via targeting ICER in CTLA-4 positive T cells using MSNs loaded with anti-ICER small interfering (si)RNA decorated with oligopeptides spanning specific paratopes trapping CTLA-4. Importantly, these peptides are meant not only to guide ICER RNAi delivery into CTLA-4 positive T cells but also to serve as functional CTLA-4 blockade replacing ipilimumab - clinically proven monoclonal antibody against melanoma blocking CTLA-4. It is expected that targeting ICER in CTLA-4 positive T cells will primarily circumvent regulatory T (Treg) cell`s ability to affect the potency of antigen-presenting cells (APCs) to activate tumor-specific T cells. MSNs have been approved as lead candidates for host matrices of active pharmaceutical ingredients (API) in the next generation of medicines, mostly due to their adjustable fabrication, ordered mesostructure, facile functionality, and outstanding biocompatibility. Multifunctional nanoparticles (MSNs) will be loaded with siRNA targeting ICER mRNA (payload) capable to penetrate T cells in general and CTLA-4+ T cells (helper T CD4+ and cytotoxic CD8+ T cells), some of which consist of tumor-specific CD4+ or CD8+ T cells, Treg cells, in particular, and/or APCs. The technology developed above could establish an approach to switch from the current immunotherapies based on monoclonal antibodies-driven modulation of the immune system limited to one or two checkpoints located exclusively on the cellular surface to specific exploitation of the nanotechnology exploring combinatorial immunotherapies using targeting of two or more checkpoints irrespective of their cellular localization (e.g. CTLA-4 on the cell`s surface and ICER in the cell`s nucleus).